Process for the preparation on N-substituted 6,7-methylenedioxy-4-quinolone derivatives

ABSTRACT

Novel process for producing antimicrobial 1-substituted-6,7methylenedioxy-4-quinolone-3-carboxylic acid derivatives of the formula,   WHEREIN R is alkyl or alkenyl, and R1 is hydrogen or alkyl. The novel process is shown by the following reaction schema:   WHEREIN R and R1 are as defined above; R1&#39;&#39; is alkyl; X is halogen; and Y is, for example, halogen. The 1-substituted-6,7methylenedioxy-4-quinolone-3-carboxylic acid derivative of the formula (I) can be also produced directly from the compound of the formula (II) by the reaction with the acid anhydrous or acidic substance. The quinolinium salt of the formula (III) can be, alternatively produced by the process as shown below:   WHEREIN R, R1&#39;&#39;, X and Y is as defined above.

i United States Patent [1 1 Nakagomeet al.

[ PROCESS FOR THE PREPARATION ON N-SUBSTITUTED 6.7-ME'I'HYLENEDIOXY-Ai-QUINOLONE DERIVATIVES [76] Inventors: Takenarl Nakagome. No. I] II 9-chome. Honmachi, Toyonaka; .Hldeo Agui, No. 9- l7. 4-chome,

Sakuragaoka. Minoo. both of Osaka; Toru Mltani, No. 28-16. 3-chome, Koshienguchi, Nishinomiya; Mltsuo Nakashlta, No. 4-22. 2-chome, Oishihigashimach Nada. Kobe. both of Hyogo. all of Japan [22] Filed: Apr. 2, 1973 [21] Appl. No.: 347,029

Related US. Application Data [62] Division of Ser. No. 53,706, July 9. I970. Pat. No.

[30] Foreign Application Priority Data July 9, 1969 Japan 44-54661 Oct. 2. 1969 Japan 44-54890 Nov. I2, 1969 Japan 44-79408 Nov. I2. 1969 Japan 44-74909 Nov. I2. 1969 Japan 44-79410 Nov. 12, l969 Japan 44-90957 Feb. 23, 1970 Japan 4545722 Nov. 4, 1975 substituted-6,7-methylenedioxy-4-quinolone-3- carboxylic acid derivatives of the formula.

0 o 000R u O wherein R is 'alkyl or alicenyl, and R is hydrogen or alkyl.

2 Claims, No Drawings 1 2 PROCESS FOR THE PREPARATION ON wherein R and R are as defined above; R, is alkyl; N-SUBSTITUTED X is halogen; and Y is, for example, halogen. The METHYLENEDIOXY-4-QUINOLONE 1-substituted-6,7-methylenedioxy-4-quinolone-3- DERIVATIVES 5 carboxylic acid derivative ofthe formula (1) can be also produced directly from the compound of the for- This is a division of application Ser. No. 53.706, filed mula (ll) by the reaction with the acid anhydrous or July 9, l970,now U.S. Pat. No. 3,761,482. acidic substance.

The novel process of the present invention is shown The quinolinium salt of the formula (ill) can be. by the following reaction schema: alternatively produced by the process as shown below:

' hydrogenation catalyst ROH NH TH a c cooa II a en I /COOR 1| (In c n o-cmc aci d anhydrous or o 1 acidic substance m 0 9 czooa H2O or alcohol cooa H o cooa" v COOR1' H or :@NH N (VII) (.VIII) halogcnating agent x I cooa nlkylatlng agent R wherein R, R., X and Y is as defined above. (III);

BACKGROUND OF THE INVENTION I l Iii R wherein R is alkyl or alkenyl and R. is hydrogen or alkyi. and to novel compounds useful as intermediates for their production.

The term alkyl as used throughout this specification means straight or branched chain alkyl radicals having from one to carbon atoms. The term alkenyi refers to alkenyi radicals having from two or four carbon atoms.

Preferred examples of R and R. are alkyi radicals of not more than 4 carbon atoms. for example, methyl ethyl. n-propyl. n-butyl. isopropyl. isobutyl or secondary butyl radicals, in terms of both the antibacterial activity of the product and the readiness with which the reaction proceeds.

2. Description of the Prior Art it has been known that the l-substituted-6.7- methylenedioxy-4-quinoione-S-carboxylic acids are useful as antimicrobials (see. for example, Japanese Pa- 4 1 diethylotiioxymsthylenemsionste cooc a,

hosting o )j cooc u 11.

O N- ikyiliion hydrolysis l H cooc n o coca N-slitylstlon I-subItitutQd-G.1-meihylenodioxy -4 qulnoione-I-carboxylic acid.

This prior art process includes N-alkylation of either 3-ethoxycarbonyl-6.7-methylenedioxy-4- hydroxyquinoiine or 6,7-methylenedioxy-4-hydroxy-3- quinoline-carboxylic acid. it has been found, however, that such N-alitylation is disadvantageous in that the reaction necessitates the use of sodium hydride, which is very troublesome to handle: and further requires the use of a large amount of alkylbromide or alkyliodide, both of which are very expensive. in addition. the yield obtained in the cyclization of diethyl 3,4- methylenedioxy-anilinomethyienemalonate to ethyl -4- hydroxy-6,7-methylenedioxy-B-quinolinecarboxylate is poor.

SUMMARY OF THE INVENTION Applicants, on the other hand, have developed a novel and advantageous method for the production of l-substituted-6.7-methylenediioxy-4-quinolone-3- carboxylic acid derivatives. According to the present invention, i-substituted-6.7-methylene-dioxy-4- quinoione-3-carboxylic acid derivatives of formula (l) 5 can be produced very economically and advantageously by reaction 3,4-methyienedioxyaniline with an alcohol in the presence of a conventional hydrogenation catalyst, preferably a Raney nickel catalyst. to yield an N-substituted-3,4-methylenedioxyaniline. condensing the obtained N-substituted-3.4-aikoxycarbonyi-with a dialkyl ethoxymethyienemalonate to yield a diaikyi N-substituted-3.4-me'thylenedioxyanilinomethylenemaionate. and cyclizing the obtained dialkyl N substituted-3.4-methylenedioxyanilinomethyienemaionate in the presence of a condensing agent selected from the group consisting of an acid anhydride, an acidic substance and a mixture thereof to yield a lsubstituted-6,7-methylenedioxy-4-quinolone-3 carboxylic acid or its ester, either directly or through an intermediate N-substituted 3-alkoxycarbonyl-6,7- methylenedioxy-quinoiinium rsalt. All of the above rcactions proceed in high yield and require a reagent 3,917,605 S 6 yanillnomethylenemalonatc or a 3-alkoxycarbonyl-4- u (1). Another ob ect of the present invention is to proy yy yq ,wlth a haloge' vide novel compounds which are useful for the produc- 2 7 8 8 y y l 8 tion of the l-substituted 6,7-methylenedioxy-4- "melhylcnedloxyqumohne and reacting the quinolone-B-carboxylic acid derivatives of the formula ned :a k yc 0 y 0g (l). Other objects and merits of the present invention mclhylinedloxyqumohn? with an alkylating or will be apparent from the following descriptions. kenyhllmg agem- Contrast the kmwn y in order to accomplish these objects, the present inmm rwctwn dwthyl 3Amethylvnedioxynnilinomvention provides a method for the production of the thylenemalonatc where the yield is poor. the novel f r ula method of the present invention. using a hulogenuting l0 agent, furnishes a high yield of cyclized product under much milder reaction conditions. The reaction of 3 laikoxycarbonyl-4-halogeno-6,7- l methylenedioxyquinoline with an alkylating or alkenyluting agent results in an almost quantitative yield N of the product.

whereinRisC-C alkl C-C lit 1' dR h The method of the present invention is briefly shown drogen or c d lltyh or 2 a my m I IS by the following schema' wherein R and are Further detailed descriptions concerning the reaction defined above. t l' as defined for and Y steps of the method of the present invention are given Detailed Description of the Invention is an organic or inorganic acid anion. below H t' coon, lo M NH H \N i vn vm (IV) {OORII C H O-CH COOR 0 OR E COCR I Co I N H o x COOR 0 wt O ,7 coon, gms 1/ R The aforesaid organic or inorganic anion may be ex- Reaction A-Preparation of N-substituted cmplified by chloride, bromide, iodide, sulfate. phos- 3,4-rnethylenedioxyanilines phate, nitrate, perchlorate, borofluoride. formatc, acetatc, propionate, oxalate, succinatc, alkylsulfate, alkyl- In the reaction of ihe Present invention lf r l lf at or th lik H w v r, th methylenedioxyaniline is contacted with an equivalent amples are not limitativc but only illustrative. '8" amount of an alcohol 0f the formula H. Among the compounds produced by our method, wherein R is as defined above, at a temperature of N-C,., -alkylor N-alknyl-B.4-methylenedioxyanilines -2 preferably 50-l50C. in the presence of a of the formula (IV), N-alkyl-or N-alkenyl'3.4- conventional hydrogenation catalyst, preferably a methylenedioxyanilinomethylenemalonatcs of the for- Raney nickel catalyst. Use of an excess of the alcohol 'mula (ll), 3-alkoxycarbonyl-4-halogono-6,7- does not prevent the progress of the reaction. The methylcnsdloxyquinolinel of the formula (Vi) and amount of the catalyst is not limited. It is preferred to their N-ttlltylatcd or N-ulkcnylatcd quaternary ammousc l/l00 or more part of the catalyst. based on the nium salts of the formula (iii) are novel compounds. weight of the 3.4-mcthylenedioxyaniline. The reaction Accordingly, an object of the present invention is to may be carried out in the presence of an inert solvent provide a novel and advantageous method for the prosuch as benzene, toluene, xylene, an other, hexane. peduction of l-substitutcd 6.7-methylenedioxy-4- trolcum ether. ligroin. an alochol. and water. it is espequlnolonc-Il-carhoxyllc acid derivatives of the formula cially preferred to use as the solvent the same alcohol used as the alkylating or alkenylating agent. it is also preferred to carry out the reaction under an atmosphere of inert gas. because when 3.4- methyiencdioxyaniline and the prepared N-alkyl-3.4- methyienedioxyaniline are contacted with air. they are considerably colored.

3.4-Methylenedioxyaniiine used as the starting substance is known compount and produced. for example, by reducing 3.4-methylenedioxynitrobenzene. So. in case this reduction is carried out by catalytic hydrogenation in the presence of an alcohol. it is possible to conduct the alkylation or aikenylation of the present invention consecutively following the reduction by heating of the reaction mixture at a suitable temperature.

The N-substituted-3.4-methyienedioxyaniiine thus obtained is a colorless and fluid liquid and soluble in organic solvents. such as alcohols. benzene. chloroform and ethers.

The N-substituted-3.4imethyienedioxyanilines obtained by the present invention are novel compounds except for N-methyl-3.4-methylencdioxyaniline. N- Methyi-3.4-methyienedioxyaniiine has been produced previously by heating o-methylaminopiperonylic acid in the presence of copper powder or acylating 3.4- methylenedioxyaniline. treating the obtained 3.4- methyienedioxyacetanilide with methyliodide and alkali and then hydrolyzing the resultant N-methyl-3.4- methylenedioxyacetanilide. These known processes. however. necessitate the use of very expensive materials and complicated operations. and are therefore not industrially advantageous. In contrast to the above procedure. the method of the present invention is very advantageous in that it is possible to produce the desired N-substituted-3.4-methyicnedioxyaniline from 3.4- methylenedioxyaniline in high yield in a single step.

Reaction B-Preparation of diaikyl N-substituted-3.4-methylenedioxyanilinomethylenemalonates of the formula (ll) Dialkyl N-substituted-3.4-methylenedioxyanilinomethyicnemalonates of the formula (ll) can be produced by a conventional method. that is. by reacting an N- substituted-3.4-methylenedioxyaniline with an equimolar amount of a dialkyl ethoxymethyienemalonate at a temperature of 50-200C. The reaction is carried out. if necessary. in the presence of an inert solvent. such as toluene. benzene. diphenyl. diphenyl ether. mineral oil. etc. The yield is almost quantitative.

Reaction C-Preparation of N-substituted-6.7-methylenedioxy-4-quinoline-3- carboxylic acid derivatives of the formula (i) A dialkyl N-substituted-3.4-methylenedioxyanilinomethyienemalonate of the formula (ii) is contacted with an acidic compound or an acid anhydride selected from the group consisting of phosphorus pentoxide. acetic anhydride propionic anhydride. sulfuric acid. poiyphosphoric acid. polyphosphoric acid ester. phosphorus oxyhaiide such as phosphorus oxychloride and phosphorus oxybromide. phosphorus trichioride. phosphorus tribromide. phosphorus pcntachioride. thionylchloridc. a flaorinated boron compound. such as boron triilaoride. chloromethylcnedimcthyiammonium chloride or the like. and a mixture thereof at a temperature of O-200C. preferably 50-l50C. The reaction may be carried out in the absence of a solvent. However. it is possible and preferable to conduct the reaction in the presence of an inert solvent in order that the reaction be conducted smoothly in a homogeneous reaction system. Examples of such inert solvents include ether halogenated hydrocarbons and petroleum soivents. One equivaient amount of an acidic compound or an acid anhydride is required for the cyclization reaction. Use of an excess of condensing agent, however. does not prevent the progress of the reaction.

Found particularly useful is phosphorus oxychloride. poiyphosphorie acid ester or a iiluorinated boron compound each of which gives the desired product in especially'high yield. Preferred are phosphorus oxychloride and poiyphosphoric acid ester. which not only can be used as the solvent in the cyclization reaction but also are miscible with most organic solvents. An excess oi phosphorus oxychloride can be recovered easily by reduced pressure distillation.

The cyclization reaction produces both or either one of the N-substituted-6.7-methylenedioxy-4-quinolone- 3-alkoxycarbonyl derivatives of the formula (I) in which R. is alkyl and N-substituted-6.7- methylenedioxy-4-quinoione-3-carboxylic acid derivatives of the formula (I) in which R. is hydrogen, depending upon the reaction conditions. The two reaction products can be easily separated from each other.

The product is usually an N-substituted-6.7- methylenedioxy-4-quinolone-3-alltoxycarbonyl derivative when an acid anhydride. a Lewis acid or phosphorus oxyhaiide is used as a cyclizing agent. N- substituted-6.7-methylenedioxy-4-quinoione-3- carboxyiie acid may be formed 'when the cyclization reaction is effected at above C in the presence of an acid. e.g polyphosphorie acid or sulfuric acid.

Should an N-substituted-3-alkoxycarbonyl-6.7- methylenedioxy-4-quinolone be obtained, it can be hydrolyzed to the corresponding free acid according to conventional methods.

if so-calied halogenating agents, such as phosphorus oxhalide. phosphorus pentachloride. phosphorus trichloride or thionylchloride. are used as the cyclization agent. there may be formed an N-substitutcd- -aikoxycarbonyl-4-haiogeno-6.7- methylenedioxyquinolinium salt of the formula (iii). wherein Y is halogen. as an intermediate.

The intermediate can be isolated as an iodide or perchlorate when one of hydrogen iodide, hydrogen perchlorate or their salts is added to an aqueous solution of the reaction product.

in this case the N-substituted-A-halogeno-6.7- methylenedioxy-S-alkoxycarbonyiquinolinium salt is reacted with water or an alcohol of the formula, R,OH. wherein R, is hydrogen or aikyl. to give the objective N-substituted-6.7-methylenedioxy-4-quinolone-3- carboxylic acid derivative of the formula (l) in a high yield. This reaction is carried out at a temperature of 0-200C. preferably 50-l20C and it is preferred to use an acid or a base in order to accelerate the raction. Examples of acids which may be used include inorganic acids suchas. for example. hydrochloric acid. sulfuric acid and phosphoric acid and organic acidic compounds. such as. for example phenol. formic acid. acetic acid. propionic acid. aikylor arylsulfonic acid and alkylsulfonate. Examples of bases which may be used include inorganic bases such as. for example. alkaii or alkaline earth metal hydroxides. carbonates or bicarbonates. alkali or alkaline earth metal salts of organic acids. organic bases such as. for example. pyridine. triethyiamine and triethanoi amine and quaternary ammonium salts of said organic amines. it is possible to conduct the reaction in the presence of a solvent coon. c

COOR m EH \O i if wherein R. is as defined above. or a 3-alkoxycarbonyl- 4-hydroxy-6.7-methylenedioxyquinoline of the formula.

OH OOR1' CH2 tvm) wherein R. is as defined above. with a halogenating agent to yield a 3-alkoxycarbonyl-4-halogeno-6.7- methylenedioxyquinoline of the formula.

COOR 1 CH2 wherein R, is as defined above. and then reacting the obtained 3-alkoxycarbonyl-4-halogeno-6.7- methylenedioxyquinoline with a suitable alkylating or alkenylating agent. The procedures for the preparation of these compounds areillustrated as follows.

Preparation of the 3-alk0xycarbonyl-4-halogeno-6.7- methylenedioxyquinolines of the formula (VI) in the present invention, a 3.4-methylenedioxyanilinomethylenemalonate of the formula (Vll) or a 3-alkoxycarbonyl-4-hydroxy-6.7- methylenedioxyquinoline of the formula (VIII) is reacted with a halogenating agent.

Examples of such halogenating agents include phosphorus oxychloride. phosphorus oxybromide. phosphorus pentachloride. phosphorus trichloride. phosgene or thionylchloride. ehloromethylenedimethylammonium chloride or a mixture thereof. The reaction of the 3.4- methylenedioxyanilinomethylenemalonate or the 3- alkoxycarbonyl-4-hydroxy-6.7- methylenedioxyquinoline with the halogenating agent is carried out at a temperature from room temperature to 200C. preferably 50-l50C. Though the reaction proceeds even when carried out in the absence of a solvent. it is preferable to use an inert solvent such as. for

example. toluene. benzene. chlorobenzene. dichloroethane. chloroform. other. petroleum hydrocarbon. etc.. or to use excess of the halogenating agent as a solvent. in order to carry out the reaction smoothly. The presence of an amine. such as pyridine. diethylamine. 'etc.. accelerates the reaction rate.

Preparation of N-substituted-3-alkoxycarbonyl-4-halogeno-6.7- methylenedioxyquinolinium salts of the formula (iii) A 3-alkoxycarbonyl-4-halogeno-6.7- methylenedioxyquinoline is contacted with an equimolar or larger amount of an appropriate alkylating or alkenylating agent to yield the desired compound. Examples of such alkylating agents include alkyl sulfates. such as dimethyl sulfate. diethyl sulfate and ethyl p-toluenesulfonate. alkylearbonates. such as dimethyl carbonate. and alkylhalides. such as methyliodide. ethyliodlde. ethylbromide. butylbromide. isohutylbromidc. propyliodide. hexyiiodide. decylbromide. dodecylbromide and triethyloxonium fluoborate.

Examples of such alkenyiating agents include alkenylhalides. such as vinyl chloride. allyl iodide and butenylbromide. This reaction is carried out at a temperature of 0200C. preferably 25-l20C. Though the reaction proceeds even in the absence of a solvent. it is preferable to carry out the reaction in the presence of an excess of the alkylating or alkenylating agent as a solvent or in the presence of an inert solvent such as. for example. ether. benzene. toluene. chloroform. petroleum hydrocarbon. etc.

The anionic ion of the thus obtained N-substituted-3- alkoxycarbonyl-4-halogeno-6.7- methylenedioxyquinolinium salt may be converted into various other kinds of anionic ions of inorganic or organic acids. This change of anionic ion is accomplished according to conventional procedure. That is. the N- substituted-3-alkoxyearbonyl-4-halogeno-6.7- methylenedioxyquinolinium salt is treated with an ion exchange resin and mixed] with a desired inorganic or organic acid.

The present inventionis illustrated in more detail with reference to the following examples. However is should be understood that. the present invention is not limited to such examples. Various modifications within the scope of the present invention will occur to one skilled in the art.

EXAMPLE 1 Elementary analysis Found: Calculated for C..H,.NO,

b. 3.4-Methylenedioxynltrobenzene (16.7 g) and Raney nickel (3 g) were suspended in ethanol cc). into the stirred suspension. hydrogen gas was intr0- duced under atmospheric pressure until absorption of hydrogen gas ceased. Thereafter the reaction mixture was stirred and heated under reflux for 18 hours. After cooling, the catalyst was removed by filtration and the filtrate was concentrated and distilled under reduced pressure to give the colorless liquid. N-ethyl-3,4- methylene-dioxyaniline (i5.9 g, 96%). Stage 2 A mixture of N-ethyl-3,4-methylenedioxyaniline (5 g) obtained in Stage 1 and diethyl ethoxymethylenemalonate (6.5 g) was stirred and heated at 90C for L5 hours and then for 30 minutes, while reducing the inner pressure by means of an aspirator, to give pure diethyl N-ethyl-3,4-mcthylenedioxyanilinomethylenemalonatc as an oily substance. which could be used in the next stage without purification.

A part of the product was purified by silica gel column chromatography using chloroform as an eluting solvent.

Elementary analysis thylenemulonate (l 3) was dissolved in phosphorus oxychloride (40 cc) and the resultant mixture was stirred and heated at i00C for 2 hours, and then excess ofphosphorus oxychloride was removed from the mixture by reduced pressure distillation. Ice-water was added to the obtained residue. The resultant mixture was basified by the addition of an aqueous sodium hydroxide solution, and heated at 95-l00C for 3 hours. The mixture was then acidified by the addition of concentrated hydrochloric acid and cooled. The precipitate of i-ethyl 6,7-methylenedioxy-4-quinoione-3- carboxylic acid (6.7 g) was collected by filtration and recrystallized from aqueous dimethylformamide, colorless needles, mp. 3l5C (decomposition).

Elementary analysis Found Calculated for C ,H,,NO,

b. Polyphosphoric acid ethyl ester was obtained by boiling a mixture of phosphorus pentoxide (l5 g), anhydrous ether cc) and chloroform (30 cc) under refiux for hours until the mixture became transparent, filtering the mixture by means of glass-wool, and then removing the solvent from the filtrate under reduced pressure.

A mixture of the obtained polyphosphoric acid ethyl ester and diethyl N-ethyl-3,4-methyienedioxyanilinomethylenemalonate (3 g) obtained in Stage 2 was stirred and heated at i20-i C for 4 hours, while the ethanol produced was being removed by reducing the inner pressure by means of an aspirator. After the reaction was completed, the reaction mixture was poured into lee-water, basil'led by the addition of aqueous sodium hydroxide solution. The resultant mixture was stirred with heating on a bath at 95-i00C for l hour. After cooling, the mixture was acidified to pH 3 by the addition of SN-hydrochlorie acid to precipitate l-ethyl-6,7-methyienedloxy-4-quinolone-3-carboxylie acid, which was collected by filtration, washed with water and then dried. mp. 315C (decomposition). Yield: 2.51 g

c. A mixture of N-e'thyl-3,4-methylenedioxyanilinomethylenemalonate (3.45 g) obtained in Stage 2and boron trifluoride etherate (20 cc) was refluxed for 3 hours. During the reaction, a white precipitate separated. After ice-cooling, the precipitate was collected by filtration, washed with ether. and then added to an aqueous 5% sodium hydroxide solution (50 cc) and the obtained mixture stirred with heating at 80-90C for 2.5 hours. After the reaction was completed. the reaction mixture was cooled and acidified to pH 2 by the addition of hydrochloric acid. The precipitate of l-ethyl-6,7-methylenedioxy-4-quinolone-3- carboxylic acid was collected by filtration, washed with water, dried and then recrystallized from aqueous dimethyl formamide to yield colorless needles (2.1 g), m.p. 3 l 5C (decomposition).

d. Diethyl N-ethyl-3,4-me'thylenedioxyanilinomethylenemalonate (5.75 g) obtained in Stage 2 was dissolved in acetic anhydride (l4 cc). Into the resultant mixture was added dropwise concentrated sulfuric acid (7 cc) while keeping the temperature below C by cooling. After the addition, the mixture was allowed to stand for 15 minutes at room temperature and then poured into ice-water. The obtained mixture was basi fied by the addition of an aqueous sodium hydroxide solution and hydrolyzed by the procedure described in (a) above. to give l-ethyl--6,7-methylenedioxy-4- quinolone-3-carboxylic acid, map. 3l5C (decomposition).

e. Diethyl N-ethyl-3,4-methylenedioxyanilinomethylene-malonate (5 g) was added into polyphosphoric acid (25 g) and the obtained mixture was stirred and heated at -90C for l hour and thereafter mixed with ice-water 150 cc). The obtained mixture was heated at l00C for 2 hours. The resultant precipitate was collected by filtration, washed with water and dried to give i-ethyl-6,7-methylenedioxy-4-quinolone- 3-carboxylic acid, m.p. 3 l4C (decomposition.

EXAMPLE 2 Preparation of ethyl l-ethyi-6,7-methylenedioxy-4-quinoione-B-carboxylate a. Diethyl N-ethyl-3,4-methylenedioxyaniiinomethylene-malonate (5 g) obtained by the procedure disclosed in Stage 1 and Stage 2 of Example I was added to polyphosphoric acid (50 g) with stirring below room temperature. The obtained yellow and viscous mixture was heated to 85-90C with stirring and the stirring was continued for L5 hours at the same temperature. After cooling, the mixture was mixed with ice-water g) to give a homogeneous solution which was basified to pH 8-9 by the addition of an aqueous 50% sodium hydroxide solution. The precipitate produced was collected by filtration, washed with water and dried to give ethyl i-ethyl-6,7-methylenedioxy-4-quinolone-3- carboxylate (3.5 g). Recrystallization from water gave colorless needles, mp. l77C-l78C.

Elementary lnflluil Found Calculated for c,,H.,No,

13 h. Diethyl N-ethyl-3,4-methylenedioxyanilinomethylene-malonate (4.6 8), obtained by the procedure disclosed in Stage and Stage 2 of Example 1 was dissolved in phosphorus oxychloride (20 g) and the resultant l4 chloride and collecting the resultant precipitate by liltration. washing with water and drying. Recrystallization from acetone-ether gave yellow prismatic crystals which melted at l4l-l42C, and solidified by furmixture was stirred and heated at 100C for 2 hours. 5 healing and mailed again in Elementary analysis Remaining phosphorus oxychloride was removed by distillation and the residue was poured into ice-water. The resultant mixture was basified to pH 9-l0 by the addition of an aqueous sodium hydroxide solution under ice-cooling and then extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated by distillation. The residue was treated with activated charcoal and recrystallized from water to yield colorless crystals of ethyl l-ethyl-6,7-methylenedioxy-4- quinolone-Il-carboxylate (8 g), m.p. l77-l78C.

EXAMPLE 3 Preparation of l-ethyl-3-ethoxycarhonyl- Alkali Water Reaction l-ethyl-oJ-methylene- 4-chloro-6,7-mcthylenc- Time temp. diox \'-4-quinolone-3- dioxyquinolinium iodide carhoxylic acid b l.l'l g Nu CO 25 cc 6 hrs. H) g 2.5 g c Lit g cc of 5'2 5 min, I l g aqueous NaOH solution d l.l' g 20 cc 4 hrs. 1.05 g

l-cthyl-o,7-methylenedioxy-4-quinolone-3-carboxylic EXAMPLE 4 acid 40 Preparation of Slug? 1 l-ethyl-6,7-methylenedioxy-4-quinolone-S-carboxylic Diethyl N-ethyl-3,4-methylenedioxyanilinomethyacid lene-malonate (40 g) was added into phosphorus oxy- Stage I chloride 160 cc), and the obtained mixture was stirred a. methyl 34 mehylcncdioxyanilinomethylenema and heated at 75C for 3 hours. After the reaction was over, excess of phosphorusoxychloride was distilled off under reduced pressure. The resultant residue, containing l-ethyl-3-ethoxycarbonyl-4-chloro-6,7- methylenedioxyqulnolinium chloride, was dissolved into ice-water and potassium iodide g) was added to give a pale yellow precipitate of l-ethy1-3- ethoxyearbonyl4-chloro-6.7-

methylenedioxyquinolinium iodide, which was collectcd by filtration, washed with water and dried, yield lonate (30 g) was added into phosphorus oxychloride (240 cc) and the mixture was stirred and heated at 95C for 3.5 hours. The phosphorus oxychloride was removed by distillation under reduced pressure and the obtained residue was poured into ice-water, and neutralized with an aqueous sodium carbonate solution. The yellow precipitate that separated was collected by filtration, washed with water and dried, yield 26.2 g. Recrystallization of the product from ethanol gave col- 0 orless prismatic or needle-like crystals of ethyl 4- 47 (dccomposmom' chloro-6,7-methylenedioxy-3-quinoline carboxylatc,

m.p. lO9-l09.5C.

Elementary analysis a rm c 4|.2w H 3.40% N 3.41% Element mm m c.,H,.N0,c|T c 41.36% H 3.4% N 3.21% 2: A for C 55-69% H N c,,H,.,No,c| c 55.86% H 3.60% N 5.01%

The l-ethyl-3-ethoxycarbonyl-4-chloro-6,7-methylene-dioxyquinolinium chloride mentioned above was converted into a corresponding perchlorate by adding pcrchloric acid into a cold aqueous solution of the b. Ethyl 4-hydroxy-6,7-methylenedioxy-3-quinolinecarboxylate (26 g) was added into phosphorus oxychloride (200 cc) and the obtained mixture was stirred and heated at 95C for 3 hours. Worked up according to a procedure similar to that of above-mentioned procedure (a). ethyl 4-chloro-6.7-methylenedioxyquinoline- 3-carboxylate g) was obtained. m.p. 109C. Stage 2 a. Ethyl 4-chloro-6.7-methylenedioxy 3- quinolinecarboxylate (2.l g) obtained in Stage I was added into ethyl iodide (20 cc) and the mixture was heated under reflux for 46 hours. The mixture was diluted with acetone and cooled. The precipitate was collected by filtration and washed with acetone to give pale yellow-colored l-ethyl-3-ethoxycarbonyl-4- chloro-o,7-methylcnedioxyquinolinium iodide. m.p. l87-l88C (decomposition).

lilementa y analysis Found G 4mm H 3.4m N 3.41% Calculated for t. ,H..No.cu c 41.36% H 3.4% N 3.2m

The iodide thus obtained was converted to the corresponding perchlorate by adding an aqueous perchloric acid solution to a methanolic solution of the said iodide 2 and collecting the resultant crystal. Recrystallization from acetone-ether gave the pure product which melted at 14 l-l 42C. solidified by further heating and then melted again at 160C.

5 reflux for 3 hours.

EXAMPLE 5 Preparation of ethyl l-methyl-6.7-methylenedioxy-4-quinolone-3- carboxylate Stage 1 A mixture of ethyl 4-chloro-6.7-

methylenedioxyquinoline-3-carboxylate (5g), dimethyl sulfate (7.3 g) and benzene cc) was heated under l-Mlethyl-B-ethoxycarbonyl-4- chloro-6,7-methylenedioxyquinolinium methosulfate precipitated on cooling the mixture. The precipitate was collected by filtration, washed with benzene and then with acetone. m.p. l87-l88C. (decomposition) Elementary analysis Found C 44.10% H 3.70; N 3.45 CI I138? Calculated for C, H,, NO,('I C 4413" H 3.7; N 3.43; Cl "-38% b. To a solution containing 4.95 g of ethyl 4-chloro- 6,7-methylenedioxy-3-quinolinecarboxylate obtained in Stage 1. 20 cc of diehloroethane and 5 cc of chloro form was added 3.8 g of trlethyloxonium fiuoborate. The resultant mixture was heated with stirring at 50C for IS minutes and cooled in an ice bath. The crystalline solid which separated was collected by filtration and washed, with chloroform, yielding 5.4 g (77%) of l-ethyl-3-ethoxycarbonyl-4-chloro-6,7- methylenedioxyquinolinium fiuoborate, m.p. l42-l46C. Recrystallization from acetone-ether gave colorless prisms. m.p. l53-l55C.

Elementary nnalysll l-Methyl-3-ethoxycarb0nyl-4-chloro-6,7-methylenedioxy-quinolinium methosulfate (2 g) obtained in Stage l was dissolved in ethanol (20 cc). The solution obtained thus was boiled under reflux for 6 hours and then the ethanol was distilled oft. The resultant residue was washed with a cold aqueous sodium bicarbonate solution and collected by filtration to give ethyl l- Elcmcntury unulvsls Found c 45.39% H 3.75% N 3.60% (19.21% Calculated for (,,.H. .0.NBF.C| C 45.57; H 3.79; N 1.54% Cl 8.98%

Stage 3 methyl-6,7-methylenedioxy-4-quinolone-S-carboxylate :1. According to the procedure of Stage (2) of Example 3. l-cthyl-6,7-methylenedloxy-4-qulnolone-3- carboxylic acid was obtained from l-ethylethoxycarbonyl-4-chloro-6,7-methylenedioxyquinolinium iodide.

(1.25 g)..m.p. 2o2-2o3c.

Elementary analysis Found Calculated for C H ,O.N

EXAMPLE 6 Preparation of l-methyl-6.7-methylenedioxy-4-quinolone-3- carboxylic acid l-Methyl-3-ethoxycarbonyl-4-ehloro-6.7-methylenedioxy-quinolinium methosulfate (2 g) obtained by a procedure similar to that in Stage 1 of Example 5 was added into 5%-hydrochloric acid cc) and the ob tained mixture was refluxed for I hour. After cooling. the precipitate of l-methyl-6.7-methylenedioxy-4- quinoline-B-earboxylic acid was collected by filtration. m.p. 341-343C (decomposition).

Elementary analysis Found C 511.52; H 3.47% N 6.00; Calculated for C,,H.,O,N C 58.30% H 3.67; N 5.67;

EXAMPLE 7 Preparation of ethyl-6.7-methylenedioxy-4-quinolone-3'carboxylate A mixture of l-ethyl-3-ethoxycarbonyl-4-chlore-6.7- methylenedioxyquinolinium iodide (1.8 g). Sodium bicarbonate (2.5 g) and water (50 cc) was heated at 95 100C for minutes. Ethyl l-ethyl-6.7- methylenedioxy-4-quino1one-3-earboxylate precipitated on cooling the mixture. The precipitate was collected by filtration. washed with water and dried. m.p. |77-17sc. yield 1.2 g.

Elementary analysis Found C 62.38% H 5.09! N 4.951 Calculated for C H O N C 62.28% H 5.23! N 4.84)

EXAMPLE 8 EXAMPLE 9 Preparation of l-ethyl-6.7-mcthylenedi0xy-4quino1one-3-earboxylic acid Diethyl N-ethyl-3.4-methy1enedioxyanilinomethylcnc-malonate (20 g) was added into phosphorus oxychloride 100 g) and the resultant mixture was stirred and heated at 75C for 3 hours. Excess of phosphorus oxychloride was distilled off and the residue containing l-ethyl-3-cthoxycarbonyl-4-ehloro-6.7- methylenedioxyquinolinium chloride was poured into .water (500 cc). the resultant mixture was heated under reflux and then cooled. The precipitate of l-ethyl-6.7 methylenedioxy-4-quinolone-3-carboxylic acid wa: collected by filtration. mp. 315C (decomposition) Yield 14.5 g.

EXAMPLE 10 Preparation of l-ethyl-6.7-methy1enedi0xy-4-quinolone3-carboxylic acid Ethyl l-ethyl-6.7-methylenedioxy-4-quinolone-3 carboxylate (3.6 g) was suspended in an aqueous 5 sodium hydroxide solution (50 cc) and the obtuinct suspension was heated on a boiling water bath for l hour. After cooling, the mixture was acidified to pH 1-2 by the addition of hydrochloric acid. The resultant precipitate of lethyl-6.7-methylenedioxy-4-quinolone-3 earboxylic acid was collected by filtration. washed witl water and dried. m.p. 314C (decomposition). Yield quantitative. Recrystallization from dimethyl formamide gave colorless needles of m.p. 317C (decomposition).

Elementary analysis Found C 59.1(1'1 H 4.10% N 5 30'4 Calculated for C H NO 59.7766 H 4.24; N .36%

EXAMPLE 1 1 According to the procedure of Stage 1 of Example 1. except that a mixture of 3.4-methylenedioxyaniline (25 g). Raney nickel (5 g) and methanol cc) was boiled under reflux for 10 hours instead of the mixture of 3.4-

methylenedioxyaniline (24.8 g). Raney nickel (5 g) and ethanol (80 cc) being boiled under reflux for IS hours. there was obtained N-methyl-IlA methylenedioxyaniline (yield b.p. i l5-l l8/0.l mmHg.

What is claimed is:

1. A process for producing l-substitutcd-6.7-

methylenedioxy-4-quinolone-3-carboxylic acid compounds of the formula (1).

wherein R is C,.., alkyl and R, is hydrogen or C.. alkyl which comprises the steps of reacting a dialkyl-N- substituted-3.4-methylenedioxyanilionmethylenemalonate of the formula (V).

o COOR. Oct.

COOR 1 wherein R is as defined above and R, is the same alkyl as defined in R,, with a condensing agent capable of cyclizing said dialkyl-N-substituted-3.4- methylenedioxyanilinome thylencmalonate. said condensing agent being selected from the group consisting of polyphosphoric acid. polyphosphoric acid ester and mixtures thereof, at a temperature of 200C. to yield one of the group consisting ofa l-substituted-6.7- methylenedioxy-4-quinolone-3-carboxylic acid compound of the above Formula (I) wherein said R, is hydrogen and a l-substituted-6.7-methylcnedioxy-4- quinolone-B-alkoxycurbonyl compound of the above formula (I) wherein said R, is said C alkyl.

2. A process for producing l-substituted-GJ- methylenedioxy-4-quinolone-B-carboxylic acid compounds of the formula (l).

wherein R is C alkyl which comprises the steps of:

u. reacting 3.4-methylcnedioxyaniline of the formula.

with an alcohol of the formula R OH wherein R is as defined above. in the presence of Raney nickel to yield an N-substituted-3.4-

methylenedioxyaniline of the formula (IV).

b. reacting the obtained N-substituted-3,4-

methylenedioxyaniline with a dialkyl ethoxymethylenemalonate of the formula (IIXJR en 0 or c wherein R, is C alkyl, to yield a dialkyl N-substituted- 3.4-methylenedioxyanilinometihylenemalonate of the formula (II) coon, cooR II (II) o/ E/CR d. hydrolyzing the thus obtained compound.

ni nn- 

1. A PROCESS FOR PRODUCING 1-SUBSTITUTED-6,7-METHYLENEDIOXY-4-QUINOLONE-3-CARBOXYLIC ACID COMPOUNDS OF THE FORMULA (I),
 2. A process for producing 1-substituted-6,7-methylenedioxy-4-quinolone-3-carboxylic acid compounds of the formula (I), 